The proposed new investigations will employ clinical psychopathological and genetic-familial methods in a sample of over 1,000 patients. Our efforts thus far have resulted in clarification of issues regarding classification, diagnosis, and etiology of affective disorders. Psychopathological and genetic methods have been refined, especially those methods pertinent to testing the validity of nosologic classes. The results from our Pilot Clinical Study of 150 inpatients provide information as to frequency and intensity of symptoms and relative diagnostic occurrence of major nosologic classes within the affective disorders. Further progress in testing of hypotheses requires comprehensive and complex designs for studying large samples of patients, relatives and normals. This research grant application proposes two major sets of studies - clinical psychopathology studies and genetic and family studies. The basic hypothesis common to sets of studies is that the affective disorders are heterogeneous as regards etiology, clinical features, and response to treatment. Precisely defined homogeneous nosologic classes, validated by multiple external correlates, will facilitate identification of risk factors for epidemiological studies, and verification of hypotheses as to etiology and pathogenesis.